Bone is the most common site of prostate cancer metastases, and prostate cancer with bone metastases is incurable. We propose to study which aspects of the tumor cells and the bone environment affect the development of bone metastasis in prostate cancer, which will improve risk prediction for patients and create new opportunities for preventing disease progression. We will also relate dietary factors and obesity to these tumor and bone characteristics to identify opportunities for primary and secondary prevention. We will leverage a unique cohort of men in the Health Professionals Follow-up Study and Physicians' Health Study for whom a biorepository of prostate tumor specimens and long-term follow-up data already exist. In addition, we will link this tumor tissue data to stored blood samples and questionnaire data on diet and lifestyle in the Health Professionals Follow-up Study. We hypothesize that primary tumor expression of bone-related genes may promote bone metastasis by facilitating prostate cancer cells' ability to home to, survive, and grow in bone tissue. We plan to use already collected whole genome mRNA expression data to study how bone-related gene expression relates to survival, and whether it adds predictive information beyond stage and Gleason grade. In addition, we hypothesize that men who have higher levels of bone turnover, or the on-going rebuilding of bone that all adults experience, are at higher risk for bone metastases because their bone environment facilitates the growth of disseminated tumor cells. We will study this hypothesis by measuring levels of several bone-regulating hormones and markers of bone turnover in men from blood samples collected prior to their cancer diagnosis, and relating these blood markers to prostate cancer survival. We will also assess how these blood markers of bone metabolism might have affected primary tumor cell expression of bone-related genes. Finally, we hypothesize that some risk factors for advanced prostate cancer, including obesity and dietary factors like calcium, vitamin D, phosphorus, and vitamin K, may impact prostate cancer progression through their effects on tumor expression of bone-related genes and on bone turnover and the skeletal environment. Rich dietary and lifestyle data available in the Health Professionals Follow-up Study allow us to link information on diet and obesity prior to prostate cancer diagnosis with tumor characteristics and circulating bone metabolism markers. Traditionally, risk factors for prostate cancer have been viewed in light of their direct effects on the prostate. We believe that studying them in light of their effets on tumor-bone interaction might elucidate the underlying mechanisms and improve opportunities for prevention of bone metastases in prostate cancer. Overall, this study will provide a wealth of information on tumor and bone characteristics that promote prostate cancer progression, providing improved risk prediction for patients and providing new approaches to the prevention and treatment of bone metastatic prostate cancer.